Summary It is estimated that 30-60 million Americans with Type I or Type 2 diabetes would benefit from therapies that promote expansion and enhance protection of functional beta cell mass. However, human beta cells are stubbornly resistant to therapies that would safely expand beta cell mass in diabetic patients. Thus there is an urgent need to identify and exploit new pathways to safely expand beta cell mass. Beta cells proliferate as a natural adaptive response to increased demand for insulin, and glucose itself is an effective beta cell mitogen. Here, we will explore an exciting new pathway in beta cells, the antioxidant Nrf2 pathway, that we recently found is necessary for and augments glucose-stimulated beta cell proliferation. We have been studying glucose-stimulated gene expression for nearly two decades and have found that carbohydrate response element binding protein (ChREBP), a glucose-sensing transcription factor, is required for glucose-stimulated beta cell proliferation. Surprisingly, we also found that overexpression of the full length ChREBP? isoform amplifies, by 2 to 3-fold, rodent and human glucose-stimulated beta cell proliferation, without cell death. Our preliminary data demonstrate that ChREBP? overexpression reprograms metabolism to provide anabolic building blocks for proliferation. Remarkably, ChREBP? increases mitochondrial biogenesis, oxygen consumption rates, and ATP production. Functionally, pretreatment with ChREBP? enhances transplantation outcomes of human islets in STZ-treated NOD.SCID mice. Since gene therapy maneuvers that increase ChREBP? abundance are not practical, we focused on the pathways responsible for the remarkable ChREBP?-mediated anabolic effect. We found that the ChREBP?-mediated increase in beta cell proliferation requires the activation of the antioxidant Nrf2 pathway. Nrf2 also enhances mitochondrial content and activity, and increases anabolic metabolism. Furthermore, activation of Nrf2 is necessary for normal glucose-stimulated or adaptive beta cell proliferation, in vitro and in vivo. Strikingly, increased expression of Nrf2 is sufficient to drive rodent beta cell proliferation on a standard chow diet in vivo, and human beta cell proliferation in vitro, even in low concentrations of glucose. Importantly, several pharmacological Nrf2 activators are either approved or being tested in clinical trials for a variety of pathologies, but none address beta cell biology. Thus, Nrf2 performs a previously unrecognized critical role in the adaptive expansion of beta cells that may be exploited therapeutically. The current proposal will test the exciting hypothesis that Nrf2 increases mitochondrial and anabolic function in beta cells providing both increased capacity to proliferate and increased protection from oxidative stress. We will: 1) Elucidate the role of Nrf2 in the adaptive expansion of beta cell mass; 2) Establish whether increasing or decreasing Nrf2 alters human islet transplantation outcomes. 3) Explore the mechanisms by which Nrf2 promotes glucose-stimulated proliferation. !